The role of FoxO1 in interleukin-1β-induced autostimulation in retina endothelial cells and retinas of diabetic rats

- High glucose induces the expressions of IL-1β and FoxO1 in HRMECs.
- IL-1β increases the expression of FoxO1 and aggravates IL-1β autostimulation by activating MAPKs.
- Downregulation of FoxO1 by siRNA attenuates IL-1β-induced autostimulation in vitro and in vivo.
- IL-1β and FoxO1 have the potential to be a therapeutic target in diabetic retinopathy.

Diabetic retinopathy is a chronic, low-grade inflammatory disease. The present study aimed to investigate the effect of forkhead transcription factor O1 (FoxO1) expression on interleukin-1β (IL-1β)-induced autostimulation, both in vitro in human retina microvascular endothelial cells (HRMECs), and in vivo in retinas isolated from streptozotocin-induced diabetic rats. High-glucose (HG) and recombinant IL-1β treatment were both shown to increase the expression of FoxO1 and IL-1β in HRMECs in a dose-dependent manner. IL-1 receptor antagonist (IL-1RA) and mitogen-activated protein kinase (MAPK) inhibitors reduced IL-1β-induced expression of FoxO1 in HRMECs. Moreover, the increased expressions of FoxO1 and IL-1β in the retinas of diabetic rats were significantly decreased by intravitreal injection of lentiviral vector-mediated FoxO1 small-interfering RNA. Together, these results suggest that HG triggers IL-1β synthesis in HRMECs. The produced IL-1β induces increased FoxO1 expression, as well as interacts with the IL-1 receptor to activate MAPK signaling and thereby induces IL-1β autostimulation. The IL-1β-induced autostimulation can be inhibited by downregulation of FoxO1, accompanied by a reduction of inflammation. Together, these findings identify novel functions for FoxO1 and IL-1β in diabetic retinopathy.